General Anesthetics

Yacoub M. Irshaid, MD, PhD, ABCP

Department of Pharmacology

General Anesthetics

• General anesthesia is typically a state of analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation.

• This is achieved by a combination of intravenous and inhaled drugs.

General Anesthetics

Types of General Anesthesia:

A. Intravenous agents used alone, or in combination with other anesthetic agents, to achieve an anesthetic state or sedation. These drugs include:

1. Barbiturates: Thiopental, methohexital.

2. Benzodiazepines: Midazolam, diazepam.

3. Propofol.

General Anesthetics

4. Ketamine.5. Opioid analgesics: Morphine, fentanyl,

sufentanil, alfentanil, remifentanil.6. Miscellaneous sedative-hypnotics:

Etomidate, dexmedetomidine.B. Inhaled anesthetics which include:1. Volatile liquids: Halothane, isoflurane,

desflurane, enflurane, methoxyflurane, and sevoflurane.

2. Gases: Nitrous oxide.

General Anesthetics

Balanced Anesthesia:Although general anesthesia can be produced by only intravenous or only inhaled anesthetic agents, modern anesthesia typically involves a combination of:

1. IV agents for induction of anesthesia.2. Inhaled agents for maintenance of anesthesia.3. Muscle relaxants.4. Analgesics.5. Cardiovascular drugs to control autonomic

responses.

Inhaled Anesthetics

Pharmacokinetics:• An adequate depth of anesthesia depends

on achieving therapeutic concentrations in the central nervous system.

• The rate at which an effective brain concentration is achieved (time to induction of anesthesia) depends on multiple pharmacokinetic factors that influence brain uptake and tissue distribution of the anesthetic agent:

Inhaled Anesthetics

1. Uptake and distribution of inhaled anesthetics:

Achievement of a brain concentration of an inhaled anesthetic to provide adequate anesthesia requires transfer of the anesthetic from the alveolar air to the blood, and from the blood to the brain.

The rate of achievement of such a concentration depends on:

Inhaled Anesthetics

A. Solubility of the anesthetic:

• The blood:gas partition coefficient is a useful index of solubility, and defines the relative affinity of the anesthetic for the blood compared with that of inspired gas.

• The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood, are extremely low.

Inhaled Anesthetics

• Thus, when such agents diffuse from the lung into the arterial blood, relatively few molecules are required to raise its partial pressure, and therefore the arterial tension rises rapidly.

• Conversely, for anesthetics with moderate-to-high solubility (halothane, isoflurane), more molecules dissolve before partial pressure rises significantly, and arterial tension of the gas increases less rapidly.

Inhaled Anesthetics

• Nitrous oxide and desflurane (and to a lesser extent sevoflurane), with low solubility in blood, reaches high arterial tensions rapidly, which in turn results in rapid equilibration with the brain and faster onset of action.

Why induction of anesthesia is slower with more soluble anesthetic gases. In this schematic diagram, solubility in blood is represented by the relative size of the blood compartment (the more soluble, the larger the compartment). Relative partial pressures of the agents in the compartments are indicated by the degree of filling of each compartment. For a given concentration or partial pressure of the two anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be slower with halothane than with nitrous oxide.

Tensions of three anesthetic gases in arterial blood as a function of time after beginning inhalation. Nitrous oxide is relatively insoluble (blood:gas partition coefficient = 0.47); methoxyflurane is much more soluble (coefficient = 12); and halothane is intermediate (2.3).

Inhaled Anesthetics

B. Anesthetic concentration in the inspired air:

The concentration of an inhaled anesthetic in the inspired gas mixture has direct effects on both the maximum tension in the alveoli and the rate of increase in its tension in the arterial blood.

Inhaled Anesthetics

• Increases in the inspired anesthetic concentration increases the rate of induction of anesthesia.

• Advantage is taken of this effect in anesthetic practice. For example, a high concentration of isoflurane (1.5%) is used for an increased rate of induction, which is then reduced (0.75-1%) for maintenance of anesthesia.

Inhaled Anesthetics

• Similarly, moderately soluble anesthetics are often administered in combination with a less soluble agents to reduce the time needed for loss of consciousness and achievement of a surgical depth of anesthesia. (nitrous oxide + halothane).

Inhaled Anesthetics

C. Pulmonary ventilation:The rate of rise of anesthetic gas tension in arterial blood is directly dependent on both the rate and depth of ventilation. The magnitude of the effect depends on blood:gas partition coefficient.

• An increase in pulmonary ventilation is accompanied by only a slight increase in arterial tension of an anesthetic with low blood solubility, but can significantly increase tension of agents with moderate-to-high blood solubility.

Inhaled Anesthetics

• Fore example, a 4-fold increase in ventilation rate almost doubles arterial tension of halothane during the first 10 minutes of anesthesia but increases the arterial tension of nitrous oxide by only 15%.

Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2 L/min) has a much greater effect on equilibration of halothane than nitrous oxide.

Inhaled Anesthetics

• Therefore, hyperventilation increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset.

• Depression of respiration by opioid analgesics slows the onset of anesthesia of inhaled anesthetics if ventilation is not manually or mechanically assisted.

Inhaled Anesthetics

D. Pulmonary blood flow:

Changes in blood flow to and from the lungs influence transfer processes of anesthetic gases.

An increase in pulmonary blood flow slows the rate of rise in arterial tension, particularly for agents with moderate-to-high blood solubility.

Inhaled Anesthetics

• Increased pulmonary blood flow exposes a large volume of blood to the anesthetic; thus, blood capacity increases and the anesthetic tension rises slowly.

• A decrease in pulmonary blood flow has the opposite effect, increasing the rate of rise of arterial tension of inhaled anesthetics.

Inhaled Anesthetics

• In patients with circulatory shock, the combined effect of decreased cardiac output and increased ventilation will accelerate induction of anesthesia with halothane and isoflurane. This is less likely with less soluble agents such as nitrous oxide and desflurane.

Inhaled Anesthetics

E. Arteriovenous concentration gradient:• The anesthetic concentration gradient

between arterial and mixed venous blood is dependent mainly on the uptake of anesthetic by the tissue

• Venous blood returning to the lungs may contain significantly less anesthetic than arterial blood.

• The greater this difference, the more time it will take to achieve equilibrium with brain tissue.

Inhaled Anesthetics

2. Elimination of inhaled anesthetics:• The time of recovery from inhalation

anesthesia depends on the rate of elimination of the anesthetic from the brain.

• Many of the processes of anesthetic transfer during recovery are simply the reverse of those that occur during induction of anesthesia.

Inhaled Anesthetics

• The blood:gas partition coefficient of the anesthetic is one of the most important factors governing recovery, which include pulmonary blood flow, ventilation magnitude, and tissue solubility of the anesthetic.

• Two features of recovery are different from what happens during induction:

Inhaled Anesthetics

1. Although the transfer of the anesthetic from the lungs to the blood can be enhanced by increasing its concentration in inspired air, the reverse can not be enhanced, because the concentration in the lung can not be reduced below zero.

2. At the beginning of recovery, the anesthetic gas tension in different tissues may be variable. In contrast, with induction the initial anesthetic tension is zero in all tissues.

Inhaled Anesthetics

• Inhaled anesthetics that are relatively insoluble in blood (low blood:gas partition coefficient) and brain (?) are eliminated at faster rates than more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate more rapid recovery from their anesthetic effect compared to halothane and isoflurane.

Inhaled Anesthetics

• Halothane is ~ twice as soluble in brain tissue and 5X more soluble in blood than nitrous oxide and desflurane more slow elimination and less rapid recovery from halothane anesthesia.

• The duration of exposure to the anesthetic can have a marked effect on recovery time, especially for more soluble anesthetics.

Inhaled Anesthetics

• Accumulation of (isoflurane) in muscle, skin and fat increases with prolonged inhalation, and blood tension may decline slowly during recovery.

• When the exposure is short, recovery may be rapid even with the more soluble agents.

• Clearance of the inhaled anesthetics by the lungs is the major route of elimination from the body.

Inhaled Anesthetics

• Hepatic metabolism may also contribute to the elimination of halothane (~ 40% during an average anesthetic procedure).

• Oxidative metabolism (CYP2E1) of halothane results in formation of trifluoroacetic acid and release of chloride and bromide ions.

Inhaled Anesthetics

• Under conditions of low oxygen tension, halothane is metabolized to the chlorotrifluoroethyl free radical which is capable of reacting with hepatic cell membrane and producing halothane hepatitis.

• < 10% of enflurane is metabolized.• Isoflurane and desflurane are the least

metabolized of fluorinated anesthetics.

Inhaled Anesthetics

• The metabolism of methoxyflurane (70%) results in elevation of renal fluoride levels and nephrotoxicity.

• Enflurane and sevoflurane metabolism leads to formation of fluoride ions but do not reach toxic levels.

• Nitrous oxide is not metabolized by human tissues, but can be metabolized by bacteria in the GIT.

Inhaled Anesthetics

• Sevoflurane is degraded by contact with the carbon dioxide absorbent (soda lime = Ca(OH)2 (about 75%), H2O (about 20%), NaOH (about 3%), KOH (about 1%)) in anesthesia machines yielding a vinyl ether which can cause renal damage if high concentrations are absorbed.

General Anesthetics

Pharmacodynamics:

• Both the inhaled and intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain, with several potential molecular targets for anesthetic actions.

General Anesthetics

• Interaction of the anesthetics with specific nerve membrane components results in modification of ion currents, particularly the ligand-gated ion channel family.

General Anesthetics

• A primary molecular target of general anesthetics (halogenated inhalational agents, propofol, barbiturates, etomidate, ..) is the GABAA receptor-chloride channel, a major mediators of inhibitory synaptic transmission. Either it is directly activated or facilitated.

General Anesthetics

• Glycine receptor is another target for inhaled anesthetics.

• Inhalational agents enhance the capacity of glycine to activate glycine-gated chloride channels inhibitory neurotransmission in spinal cord and brain stem.

General Anesthetics

• Propofol and barbiturates, but not etomidate and ketamine, also potentiate glycine-gated currents.

• The only general anesthetics that do not have significant effects on GABAA or glycine receptors are nitrous oxide and ketamine, which act on calcium selective NMDA glutamate receptor.

General Anesthetics

• Neuronal nicotinic acetylcholine receptors inhibition by inhalational agents do not mediate anesthetic effect but mediate analgesia and amnesia.

• Certain inhalational anesthetics may cause membrane hyperpolarization by activation of potassium channels.

• Inhalational agents can produce presynaptic inhibition of neurotransmitter release in the hippocampus contributing to the amnesic effect of these agents.

Inhaled Anesthetics

Organ System Effects of Inhaled Anesthetics:

A. Effects on the Cardiovascular System:• Halothane and enflurane reduce arterial

pressure by reduction of cardiac output.• Isoflurane, desflurane, and sevoflurane

reduce arterial blood pressure by decreasing systemic vascular resistance.

Inhaled Anesthetics

• Halothane may cause bradycardia probably because of direct vagal stimulation.

• Desflurane and isoflurane increase heart rate.• All depress myocardial function, including

nitrous oxide.• Halothane, and to a lesser effect isoflurane

sensitize the myocardium to circulating catecholamines ventricular arrhythmias.

Inhaled Anesthetics

B. Effects on the Respiratory System:

• All except nitrous oxide decrease tidal volume and increase respiratory rate

• All volatile anesthetics are respiratory depressants and reduce the response to increased levels of carbon dioxide.

• All volatile anesthetics increase the resting levels of PaCO2.

Inhaled Anesthetics

• The respiratory depressant effect is overcome by assisted or controlled ventilation.

• Inhaled anesthetics depress mucociliary function of airways pooling of mucus atelectasis and postoperative respiratory infection.

• Halothane and sevoflurane have bronchodilating action (?).

• Airway irritation with desflurane.

Inhaled Anesthetics

C. Effects on the Brain:• Decrease metabolic rate of the brain.• Increase cerebral blood flow by decreasing

cerebrovascular resistance (not desirable in patients with increased intracranial pressure). Nitrous oxide is the least likely to do so.

• If the patient is hyperventilated before the volatile agent is administered, the increase in ICP can be minimized (by inducing hypocapnoeic vasoconstriction).

Inhaled Anesthetics

• Nitrous oxide has analgesic and amnesic properties.

D. Effects on the Kidney:

• Decrease GFR and renal blood flow, and increase the filtration fraction.

• Impair autoregulation of RBF.

E. Effects on the Liver:

• Reduce hepatic blood flow.

Inhaled Anesthetics

F. Effects on Uterine Smooth Muscle:

• Nitrous oxide has little effect.

• Halogenated anesthetics are potent uterine muscle relaxants.

Inhaled Anesthetics

Toxicity:1. Hepatotoxicity:• Potentially life-threatening in subjects

previously exposed to halothane.• Incidence is 1:20,000 – 35,000.• Obese patients are most susceptible.• Mechanism is unclear, but may be:

a. Direct hepatocellular damage by reactive metabolites (free radicals).

Inhaled Anesthetics

b. Initiation of immune-mediated responses by reactive metabolites. Serum of patients with halothane hepatitis contain a variety of autoantibodies against hepatic proteins.

Trifluoroacetylated proteins in the liver could be formed in hepatocytes during halothane biotransformation. They are also found in the sera of patients who did NOT develop hepatitis after halothane anesthesia.

Inhaled Anesthetics

2. Nephrotoxicity:

• Prolonged exposure to methoxyflurane and enflurane leads to formation of fluoride ions intrarenally by the renal enzyme β-lyase changes in renal concentrating ability (? proximal tubular necrosis).

Inhaled Anesthetics

3. Malignant hyperthermia:• Is an autosomal dominant genetic

disorder of skeletal muscle that occurs in individuals undergoing general anesthesia with volatile agents + succinylcholine.

• It consists of rapid onset of tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acidosis.

• It is rare but is an important cause of anesthetic morbidity and mortality.

Inhaled Anesthetics

• Associated with increased calcium concentration in skeletal muscle cells (from the sarcoplasmic reticulum). Reduced by dantrolene.

4. Prolonged exposure to nitrous oxide decrease methionine synthase activity and can potentially cause megaloblastic anemia in inadequately ventilated operating room personnel.

Intravenous Anesthetics

• Are commonly used for induction of general anesthesia because of more rapid onset than inhaled agents.

• Recovery is rapid and permits their use for short procedures.

Intravenous Anesthetics

Barbiturates

• Thiopental is the barbiturate that is commonly used for induction of anesthesia.

• Thiamylal is similar in pharmacokinetics and pharmacodynamics.

• Methohexital is shorter-acting.• Very highly lipid soluble.• After an IV bolus injection, thiopental

rapidly crosses the blood-brain barrier, and can produce hypnosis in one circulation time. Blood:brain equilibrium occurs rapidly (< 1 min).

Barbiturates

• Thiopental rapidly diffuses out of the brain and other highly vascular tissues and is redistributed to muscle and fat a brief period of unconsciousness.

• 12-16% of the dose is metabolized.• With large doses, or a continuous infusion,

thiopental produces dose-dependent decreases in arterial blood pressure, stroke volume, and cardiac output. Most likely due to myocardial depression and increased venous capacitance.

Barbiturates

• Thiopental is also a potent respiratory depressant transient apnea and lowering the sensitivity of the medullary respiratory center to carbon dioxide.

• Cerebral metabolism and oxygen utilization are decreased after barbiturate administration in proportion to the degree of cerebral depression. Cerebral blood flow is decreased but less than oxygen consumption.

Barbiturates

• Thiopental does not increase intracranial pressure and volume (unlike volatile anesthetics), and is desirable for patients with cerebral swelling.

• Methohexital can cause central excitatory activity (myoclonus), but it also has anti-seizure activity.

• Occasionally these agents precipitate porphyric crisis during induction in susceptible individuals.

Benzodiazepines

• Diazepam, lorazepam, and midazoloam are used in anesthesia primarily as premedications, because of their sedative, anxiolytic and amnestic properties, and to control acute agitation.

• Compared with IV barbiturates, these drugs produce a slower onset of CNS depression with a depth inadequate for surgical anesthesia.

• Large doses that achieve deep sedation prolong postanesthetic recovery period and can produce anterograde amnesia.

Opioid Analgesics

• Highly potent agents include fentanyl, sufentanil, and remifentanil.

• Remifentanyl is an extremely short-acting opioid, and has been used to minimize residual ventilatory depression.

• Awareness during anesthesia and unpleasant postoperative recall can occur.

• Large doses can produce chest wall and laryngeal rigidity, thereby acutely impairing ventilation and produce tolerance increasing postoperative opioid requirements.

Opioid Analgesics

• Have been used in premedications as well as adjunct to both IV and inhalational anesthesia to provide perioperative analgesia.

• The shorter-acting alfentanil and remifentanil have been used as co-induction agents with IV sedative-hypnotic anesthetics.

• Remifentanil is rapidly metabolized by esterases in blood (not plasma cholinesterase) and muscle tissue extremely rapid recovery.

Opioid Analgesics

• Can be administered in very low doses into epidural and subarachnoid space to produce excellent postoperative analgesia.

• Fentanyl and droperidol (related to haloperidol) are administered together to produce analgesia and amnesia (neuroleptanalgesia), and combined with nitrous oxide to produce neuroleptanesthesia.

Propofol

• The most popular IV anesthetic.• Its rate of onset of action is similar to IV

barbiturates but recovery is more rapid and patient ambulation is earlier.

• The patient subjectively feel better in the immediate postoperative period because of the reduction in postoperative nausea and vomiting.

• It is the agent of choice for ambulatory surgery.

Propofol

• It is used for both induction and maintenance of anesthesia as part of total intravenous or balanced anesthesia.

• It is effective in producing prolonged sedation in patients in critical care setting, but cumulative effect can lead to delayed arousal.

• Prolonged administration of conventional emulsion formulation can raise serum lipids.

Propofol

• When used in critically ill young children for sedation, it has caused severe acidosis in the presence of respiratory infection and to possible neurologic sequelae upon withdrawal.

• After IV administration, the distribution half-life is 2-8 minutes and the redistribution half life is ~ 30-60 minutes.

Propofol

• It is rapidly metabolized in the liver and excreted in urine as glucuronide and sulfate conjugates.

• Extrahepatic mechanisms may be involved in elimination.

• Less than 1% of the drug is excreted unchanged in urine.

• It produces depression of central ventilatory drive and apnea.

Propofol

• Produces a marked decrease in blood pressure during induction of anesthesia through arterial and veno dilation.

• It has the greatest direct negative inotropic effect than other IV anesthetics.

• Pain at the site of injection is the most common adverse effect after IV bolus administration (reduced by admixture with lidocaine).

Propofol

• Muscle movements, hypotonus and rarely tremors have been reported after prolonged use.

Etomidate

• It is used for induction of anesthesia in patients with limited cardiovascular reserve, because it causes minimal cardiovascular and respiratory depression and minimal hypotension.

• It produces rapid loss of consciousness.• It has no analgesic effects.• Recovery is less rapid than that of

propofol.

Etomidate

• Distribution of etomidate is rapid, with a biphasic plasma concentration curve showing initial and intermediate distribution half-lives of 3 & 29 minutes, respectively.

• Redistribution of the drug from the brain to highly perfused tissues is responsible for the short duration of action.

• It is extensively metabolized in the liver and plasma and only 2% of the drug is excreted unchanged in urine.

Etomidate

• Adverse effects:

1. High incidence of pain on injection.

2. Myoclonic activity.

3. Postoperative nausea and vomiting.

4. Inhibition of steroidogenesis with decreased plasma levels of cortisol and hypoadrenalism hypotension, electrolyte imbalance and oliguria.

Ketamine

• It produces a “dissociative anesthetic state” characterized by catatonia (muscular rigidity and mental stupor, sometimes alternating with great excitement and confusion), amnesia and analgesia, with or without loss of consciousness.

• It is chemically related to phencyclidine, a psychoactive drug with high abuse potential.

Ketamine

Mechanism of Action:May involve blockade of the membrane effects of the excitatory neurotransmitter glutamic acid at the NMDA receptor subtype.

Pharmacokinetics:• It is highly lipid soluble and rapidly

distributed into well-perfused organs, including brain, liver, and kidney.

• It is then redistributed to less well perfused tissues, with hepatic metabolism followed by hepatic and biliary excretion.

Ketamine

Pharmacodynamics:• It is the only IV anesthetic that have

both analgesic properties and the ability to produce dose-related cardiovascular stimulation.

• It stimulates the central sympathetic nervous system and, to a lesser extent, inhibits the reuptake of norepinephrine at sympathetic nerve terminals.

Ketamine

• It increases heart rate, cardiac output and arterial blood pressure which reach a peak in 2-4 minutes and decline back to baseline over the next 10-20 minutes.

• It increases cerebral blood flow, oxygen consumption, and intracranial pressure. Thus, it is potentially dangerous in patients with elevated intracranial pressure.

Ketamine

• It decreases respiratory rate but upper airway muscle tone is well maintained and airway reflexes are usually preserved.

• Its use has been associated with postoperative disorientation, sensory and perceptual illusions, and vivid dreams (called emergence phenomena).

Ketamine

• These effects can be reduced by premedication with a benzodiazepine (diazepam, midazolam).

• It is specially useful in patients undergoing painful procedures such as burn dressing.

Dexmedetomidine

• Sedative effects of the intravenous anesthetic dexmedetomidine are produced via actions in the locus ceruleus.

• It stimulates α2-adrenergic receptors at this site and reduces central sympathetic output, resulting in increased firing of inhibitory neurons.

• In the dorsal horn of the spinal cord it modulates release of substance P analgesic effects.